title: Insufficiency of BUBR1, a mitotic spindle checkpoint regulator, causes impaired ciliogenesis in vertebrates.
abstract: Budding uninhibited by benzimidazole-related 1 (BUBR1) is a central molecule of the spindle assembly checkpoint. Germline mutations in the budding uninhibited by benzimidazoles 1 homolog beta gene encoding BUBR1 cause premature chromatid separation (mosaic variegated aneuploidy) [PCS (MVA)] syndrome, which is characterized by constitutional aneuploidy and a high risk of childhood cancer. Patients with the syndrome often develop Dandy-Walker complex and polycystic kidneys; implying a critical role of BUBR1 in morphogenesis. However, little is known about the function of BUBR1 other than mitotic control. Here, we report that BUBR1 is essential for the primary cilium formation, and that the PCS (MVA) syndrome is thus a novel ciliopathy. Morpholino knockdown of bubr1 in medaka fish also caused ciliary dysfunction characterized by defects in cerebellar development and perturbed left-right asymmetry of the embryo. Biochemical analyses demonstrated that BUBR1 is required for ubiquitin-mediated proteasomal degradation of cell division cycle protein 20 in the G0 phase and maintains anaphase-promoting complex/cyclosome-CDC20 homolog 1 activity that regulates the optimal level of dishevelled for ciliogenesis.
authors.affiliation: Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Sean
authors.initials: S
authors.lastname: Porazinski
authors.forename: Huijia
authors.initials: H
authors.lastname: Wang
authors.forename: Antonia
authors.initials: A
authors.lastname: Borovina
authors.forename: Brian
authors.initials: B
authors.lastname: Ciruna
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimizu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kajii
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Makoto
authors.initials: M
authors.lastname: Furutani-Seiki
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsuura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D025063:Chromosome Disorders / Q000235:genetics / Q000503:physiopathology; D002923:Cilia / Q000378:metabolism* / Q000473:pathology*; D022083:Cytoplasmic Structures / Q000378:metabolism / Q000473:pathology*; D000072261:Dishevelled Proteins; D004285:Dogs; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009030:Mosaicism; D009990:Oryzias; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D014714:Vertebrates / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C584278:Bub1b protein, mouse; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases